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Friday, October 25, 2013

There is bad news and good news from the research literature on vitamin D. Nonspecific chronic low-back pain (CLBP) is a common condition burdening large numbers of patients worldwide, and prior research suggests that CLBP often may be associated with vitamin D3 deficiency. A newly reported study examined that hypothesis in a randomized controlled trial. Results refute the benefits of vitamin D supplementation in relieving CLBP; however, the quality and strength of evidence were very weak. In a separate study, researchers found that serum levels of vitamin D, over a wide range of values, were not associated with development of kidney stones.

In the study of vitamin D3 for chronic low-back pain (CLBP), a team of Iranian researchers conducted a double-blind, randomized, placebo-controlled clinical trial among 53 patients aged between 18–40 years (≈75% female) [Sandoughi et al. 2013]. Patients with nonspecific CLBP were randomly assigned to receive once every week for 8 weeks either oral vitamin D3 (50,000 IU; N=26) or oral placebo (N=27). Serum 25(OH)D was assessed using an enzyme-linked immunosorbent assay kit, and pain was measured using a visual analogue scale (VAS; apparently a 0–7 point scale, but this was unclear in the report).

Writing in the International Journal of Rheumatic Diseases, the researchers report that the groups were well-matched in terms of mean age, sex, and body weight. At baseline, the mean serum 25(OH)D level across all patients was 18.86 nmol/L on the first visit. After 8 weeks of intervention, mean 25(OH)D status changed from 17.88 to 27.52 nmol/L in the vitamin D group and from 19.81 to 18.91 nmol/L in the placebo group; nonsignificant P=0.25 for group differences. (Note: multiply nmol/L data by 0.40 to convert to ng/mL.)

There were statistically significant pain improvements in both groups; although, the 2 groups were mismatched on this variable after randomization. The mean VAS score for pain decreased from 5.42 to 3.03 (P=0.001) in the vitamin D group, and from 6.42 to 3.11 (P=0.001) in the placebo group. The mean changes in chronic pain were reported as 2.38 in the vitamin D group and 3.33 in the placebo group, and the difference between the 2 groups was not statistically significant.

The researchers conclude that both vitamin D3 and placebo treatments improved CLBP, but there were no significant differences in pain relief between the 2 groups of patients. However, they suggest that larger, longer-duration trials examining more diverse selections of patients are needed.

COMMENTARY:

Why didn’t vitamin D make a difference for CLBP?The benefits of vitamin D for chronic pain conditions have been extensively discussed in Pain-Topics research review papers [here] and in numerous subsequent UPDATES articles [series here]. The newly-reported study by Sandoughi et al. was a well-designed randomized, controlled trial (RCT) of vitamin D for low-back pain, with carefully selected subjects. Such RCTs assessing vitamin D are relatively rare in the literature, but most are of low quality.

Unfortunately, this RCT by Sandoughi and colleagues also is of low quality and represents weak evidence. While the article will no doubt be used in review papers or meta-analyses as evidence against the benefits of vitamin D for nonspecific CLBP, the study and its reporting were flawed in several ways that preclude its validity.

For one thing, by the researchers’ own admission, the scope of patient selection was overly narrow and the group sizes were too small to reach unbiased and reliable conclusions.

The researchers acknowledge that 8 weeks of observation was probably too short a time period, and 5 to 9 months would have been more appropriate for assessing vitamin D efficacy.

Furthermore, the researchers concur with other experts that <20 ng/mL 25(OH)D is considered to be deficient status. And, in accordance with other research, the Middle Eastern subjects in this study, predominantly females, were on average highly deficient in vitamin D at the outset (mean 7.54 ng/mL). In fact, many experts consider ≤8 ng/mL as predictive of clinical osteomalacia, which may have accounted for back pain in many subjects.

An important observation was that, after 8 weeks of intervention, 25(OH)D status remained deficient in both groups: 11.0 ng/mL in the vitamin D-supplement group and 7.60 ng/mL in the placebo group. For unexplained reasons, weekly supplementation with oral 50,000 IU of vitamin D3 barely improved serum 25(OH)D status, which raises questions about therapeutic compliance. It should be noted that many authorities suggest that 25(OH)D concentrations of 40 ng/mL or much greater are required to have an effect in reducing pain, and this present study fell way below achieving those target levels.

At the same time, both groups remarkably did report significant pain reductions on average by the end of the study; although, there were no significant differences between groups in pain relief after 8 weeks.

All of this suggests that changes in vitamin D status were insufficient in either group to be accountable for any observed improvements in back pain. Indeed, pain reductions may have been due to the natural course of CLBP in the small numbers of carefully-selected and relatively young patients, or because both groups were advised to home-exercise and allowed up to 200 mg/day of celecoxib. In the vitamin D and placebo groups, 19% and 29%, respectively, used celecoxib daily or >5-days/week. The home-exercise program and its potential beneficial effects were not assessed.

Overall, then, this study cannot be considered a reliable and valid test of vitamin D for helping patients with CLBP. It is comparable to studying an antibiotic for an infection, and observing improvement but not cure in patients receiving a dummy pill as well as in those administered a subtherapeutic dose of active drug; it is not a true test of the antibiotic’s potential.

[Note: Readers should be aware that there were numerous mathematical errors and an inconsistent use of units of measure (eg, nmol/L vs pg/mL) in the full article, which also question the reliability of results but are beyond the scope of discussion in this commentary.]

Does too much vitamin D cause kidney stones?Some research has found that vitamin D supplementation — producing increased serum 25(OH)D levels in the 40-60 ng/mL range — may be beneficial in preventing or aiding a wide range of diseases, including chronic pain conditions of various types. However, there often is an associated concern that “too much” vitamin D may increase the risks of developing kidney stones.

In a study by Stacie Nguyen — of GrassrootsHealth, Encinitas, California — and colleagues, a large group of 2,012 participants were followed prospectively for a median of 19 months [Nguyen et al. 2013]. Subjects were ≈62% females, half were ≥50 years of age, and on average they took supplements of 3,600 IU vitamin D3/day.

During the study timeframe, only 13 individuals (0.65%) self-reported kidney stones, and these were confirmed by physician diagnosis in 12 cases. The median serum 25(OH)D level among the entire cohort was 50 ng/mL and, over a wide range of values — 20 ng/mL to more than 100 ng/mL — the researchers found no statistically significant association between serum 25(OH)D and reported kidney stones (P=0.42). See Figure.

The study did reveal higher body mass index (BMI) significantly increased the odds of developing kidney stones. However, according to the researchers, individuals with high BMI need greater vitamin D intake than their leaner counterparts to achieve the same 25(OH)D serum level. Therefore, prior observations of a connection between higher vitamin D levels and kidney stones may have been related more to BMI.

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